雌激素调控的大电导钙激活钾离子通道异常表达在子宫内膜异位症发病中的作用及机制研究

Ion channel proteins involved in endometrial physiological activity, its abnormal expression or dysfunction are closely related with the pathophysiological change. the research about the role of ion channels in ectopic implantation and growth of the eutopic endometrium of endometriosis will be the new entry point of pathogenesis of endometriosis. We have discovered that the expression of large conductance Ca2 +-activated K + channel (BKCa) in eutopic endometrium of patients with endometriosis was significantly higher than the normal population, and BKCa could regulate cell cycle.the project is planned to research whether BKCa affect endometriosis eutopic endometrial cell biological characteristics, inflammatory cell recruitment and angiogenesis, and signal regulation mechanism involved in. Using animal models and in vitro experiments to determine the affection of BKCa on ectopic adhesion, invasion, proliferation of eutopic endometrium in endometriosis, and the affection on inflammatory cell recruitment and angiogenesis; Using RNA interference, specific inhibitting and activating BKCa experimental to study the change of key factors which regulate ectopic implantation of eutopic endometrium and were regulated by BKCa. Through the CHIP, the luciferase gene reporting systems, microscopic fluorescent determination and EMSA method, we study the regulation pathway of BKCa by estrogen and the signal transduction pathway by which BKCa regulate the downstream factor, to find out the pathogenesis of endometriosis in which BKCa are involved in. The project will provide the basis and methods for prevention and treatment of endometriosis.

离子通道蛋白参与子宫内膜生理活动，其表达或功能异常与机体的病理生理改变密切相关。研究离子通道在内异症发病中的作用将成为内异症发病机制研究的新切入点。本项目拟在发现内异症患者在位内膜中BKCa表达显著高于正常人群，且其参与调控子宫内膜细胞周期，并预测到BKCa的启动子区有雌激素调控的转录因子的结合位点基础上，将利用动物模型及体外细胞实验确定BKCa对内异症在位内膜异位黏附、侵袭、增殖、凋亡及局部免疫因子的影响；通过RNAi、过表达及特异性激动和抑制BKCa实验研究BKCa介导的调控在位内膜异位种植及生长的关键因子的变化；通过CHIP、荧光素酶基因报告系统、显微荧光测定及EMSA法研究内异症在位内膜细胞中雌激素调控BKCa表达的机制及BKCa调控下游相关因子的信号机制，寻找出雌激素调控的BKCa的异常表达参与内异症发病的具体机制。本课题将为预防、治疗内异症提供新的依据和方法。

大电导钙激活钾离子通道蛋白参与子宫内膜生理活动，其表达或功能异常必然参与机体的病理生理改变。在本课题研究中，课题组先行发现内异症患者在位内膜中BKCa表达显著高于正常人群，并且其通过流式细胞技术发现其参与调控子宫内膜细胞周期，进一步通过动物模型及体外细胞实验确定BKCa对内异症在位内膜异位黏附、侵袭、增殖、凋亡均有影响；研究中通过 RNAi、过表达及特异性激动和抑制BKCa实验研究BKCa介导的调控在位内膜异位种植及生长的关键因子（Integrinαvβ3、MMP-2、MMP-9、Ki67、Bcl-2、Bax、Caspase-3）的变化，确定了BKCa调控异位病灶生长的机制。